This proposal is to discover novel peptide/peptidomimetic agonist and antagonist ligands for several of the most important drugs of abuse. it will involve a three tier system of screening: (i) selection of potential ligand candidates from several peptide/peptidomimetic libraries using monoclonal anti-drug antibodies as artificial receptors; (ii) bioassays of reactive ligands using tissue specific receptor binding assays; and (iii) in vivo animal model studies. Insights into the structural nature of the most promising peptide/peptidomimetic ligands will be gained using competitive binding assays, computational modeling, X-ray diffraction, and studies of conformationally constrained/proteolytically robust analogs. This project will be the first comprehensive program to combine these theoretical and experimental approaches to advance strategies for treatment of drug addiction. Specifically, several different antibodies to cocaine, phencyclidine, morphine, and nicotine will be labeled with a fluorescent tag and used to identify sequences that bind from random peptide/peptidomimetic libraries. Three types of libraries each of approximately 3 x 10(6) diverse structures will be prepared for this purpose. All the library types will be supported on resin beads, wherein each bead of the resin hears one sequence, but nearly all the beads will display different sequences. The first library type will consist of natural amino acid pentapeptides. The second library will consist of relatively new carbamate linked structures, and the third will be a completely new type that uses urea monomers. The latter two libraries will be encoded by peptides to facilitate sequence analyses. "Active" members of all three libraries will be identified with specific monoclonal antibodies (mAb), and sequenced. Ligands that bind strongly to the antibodies, as identified in the above screen, will be prepared on a larger scale, purified, and tested for binding to the appropriate receptors. Ligands with appreciable affinity for the receptor(s) will be used in animal behavioral studies, and binding constants for the ligand antibody complexes will be determined to ascertain if these can be correlated with binding of the substrate to the appropriate receptor. Crystal structures will be determined for the most important antibody-ligand complexes, and/or binding of the antibody to the substrate will be modeled using computer graphics. This data will be used to design constrained, and proteolyticalIy stable analogs which then will be prepared and subjected to the receptor binding and behavioral assays. Potential agonists and antagonists in humans therefore will be identified.